West Nile virus (WNV) was first detected in the Western Hemisphere in 1999 in New York City. From 1999 through 2004, >16,600 cases of WNV-related illnesses were reported in the United States, of which >7,000 were neuroinvasive disease and >600 were fatal. Several approaches are under way to develop a human vaccine. Through simulations and sensitivity analysis that incorporated uncertainties regarding future transmission patterns of WNV and costs of health outcomes, we estimated that the range of values for the cost per case of WNV illness prevented by vaccination was US 20,000 dollars-59,000 dollars(mean 36,000 dollars). Cost-effectiveness was most sensitive to changes in the risk for infection, probability of symptomatic illness, and vaccination cost. Analysis indicated that universal vaccination against WNV disease would be unlikely to result in societal monetary savings unless disease incidence increases substantially over what has been seen in the past 6 years.